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Coronary ischemia-reperfusion: role of nitric oxide and endothelin-1. A Review
collateral blood vessels that interconnects arteries, and seminal observation by Furchgott and Zawadzki in 1980
under normal conditions these blood vessels have not (22), an exponential number of studies have been
functional connexions, but under some pathological performed by many researchers, in many laboratories
conditions (e. g., arterial stenosis-obstruction) may through worldwide, and using different vascular beds and
provide functional salvage pathways of potentially different experimental preparations (isolated blood
ischemic areas of the myocardium (1, 16-18). vessels, isolated organs, anesthetized and unanesthetized
animals). The intense laboratory and clinical research
After ischemia-reperfusion, the coronary circulation have let us to know that the endothelium can produce and
deserves attention because of it is damaged in different release vasodilator and vasoconstrictor substances, as
degree and it is a prime determinant of myocardial well as to know some pathways that regulate endothelial-
ischemia-reperfusion injury: it determines the area at risk, vascular smooth muscle communication (19). The
the duration of myocardial ischemia, the residual blood reading of an interesting and nice article about the history
flow through collaterals, the microvascular obstruction of this issue, related by R. F. Furchgott, is recommended
and the restoration of coronary blood flow during (24).
reperfusion. Also, the coronary circulation is the site of
cardioprotective interventions with intermittent coronary The endothelium constitutes a large organ, and it is
occlusion/reperfusion. Inadequate consideration for the formed by approximately 1013 cells, which represents 1? ,
coronary circulation might easily diminish the magnitude 5% of the total body mass (25). The endothelium derives
of differences in infarct size between the possibly from mesoderm, and in most of vascular beds it forms a
protected group and the control group (14). continuous and non fenestrated layer that covers the
internal surface of the blood vessel wall. When it is
2.2. The endothelium damaged, for instance after atherosclerosis, can be
replaced by regenerated endothelial cells that may not
The artery wall has three layers, which are termed, have the same properties as normal cells (26, 27). The
from outer to inside, adventitia, media and intima. The endothelium can produce and release endothelium-
intima is covered by the endothelium, which is a single derived relaxing factors such as nitric oxide (NO),
layer of cells lining the inside of vascular wall. Before prostacyclin (PGI2), endothelial derived hyperpolarizing
1980, the endothelium was merely considered as an factor (EDHF), hydrogen peroxide, carbon monoxide,
anticoagulant sheet of cellophane, and at present it is hydrogen sulphide, C-t natriuretic peptide, and others; of
accepted that the endothelium plays a crucial role in these factors the most relevant seem to be NO, PGI2 and
homeostasis of cardiovascular system. The healthy EDHF. The endothelium also can produce and release
endothelium is able to produce a range of substances that endothelium-derived contracting factors such as
regulate vascular tone, cellular adhesion, endothelin peptides, angiotensin II, thromboxane A2; in
thromboresistance, smooth muscle cell proliferation, and some circumstances hydrogen peroxide and prostacyclin
vessel wall inflammation (19, 20). can produce vasodilatation or vasoconstriction (19, 25).
Under normal conditions predominates the release of
In 2009 P. M. Vanhoutte wrote: “First, there was vasodilator substances, particularly NO and, in
Robert Furchgott. He simply and brilliantly demonstrated consequence, the normal endothelium is pro-vasodilator.
that endothelial cells play a pivotal role in relaxations However, under pathological conditions in which the
evoked by acetylcholine in isolated arteries, and do so by endothelium is damaged (i. e., atherosclerosis) secretion
activating muscarinic receptors of these cells” (21). In the of vasodilator substances are reduced, whereas the
late 1970s and early 1980s two cornerstone observations release of vasoconstrictor substances such as endothelin-
were made: the first, by Furchgott and Zawadzki, was the 1 (ET-1) may be augmented, the endothelium being now
discovery of the "obligatory role of the endothelium in pro-vasconstrictor (19, 25, 26) (Figure 2).
vasorelaxation by acetylcholine" (22), and the second, by
Hickey and col., was the first description and
characterization of a vasoconstrictor polypeptide
produced by endothelial cells in culture (23). From the
@Real Academia Nacional de Farmacia. Spain 17
